The field of the invention is compositions and methods relating to inhibition of N-acylethanolamine-hydrolyzing acid amidase (NAAA), and especially as it relates to treatment and prevention of pain, inflammation, and other disorders in which fatty acid ethanolamide modulation is clinically relevant.
While there are numerous compositions and methods known in the art to treat pain and/or inflammation, numerous difficulties remain. Most significantly, side effects over long administration periods and/or higher dosages often prevent successful use of such drugs. For example, certain COX-2 inhibitors have recently been implicated in adverse cardiovascular events, while aspirin-type pain medication often increases the risk of intestinal bleeding. In other examples, ibuprofen and acetaminophen tend to negatively impact hepatic function, especially at higher dosages.
Ethanolamides of long-chain fatty acids (N-acylethanolamines (NAEs)) are present in numerous lower organisms, higher organisms, and mammals with a wide variety of functions. For example, anandamide (a polyunsaturated fatty acid-type NAE), was demonstrated to have cannabimimetic activity and was reported as acting as a ligand of TRPV1 (transient receptor potential vanilloid type 1). In contrast, saturated and monounsaturated NAEs are inactive as ligands of cannabinoid receptors. However, such compounds have been reported to possess a variety of other biological activities. For example, N-palmitoylethanolamine (PEA) has anti-inflammatory, anti-nociceptive, immunosuppressive, neuroprotective, and also antioxidant activity. Interestingly, the anti-inflammatory action of N-palmitoylethanolamine could be mediated by activation of peroxisome proliferator-activated receptor-alpha (PPAR-alpha). In other examples, N-oleoylethanolamine was shown to be anorexic via PPAR-alpha (see e.g., The Journal Of Pharmacology And Experimental Therapeutics (2006), Vol. 318, No. 2, pages 563-570), and N-stearoylethanolamine to be pro-apoptotic and anorexic.
NAEs are a substrate of NAAA that catalytically hydrolyze the NAE to ethanolamine and the corresponding fatty acid. Remarkably, the catalytic activity of NAAA is significantly different from a similar enzyme, FAAH (fatty acid amide hydrolase). Among various other differences, one characteristic trait of NAAA is its activity optimum at a pH of about 5.0. NAAA also exhibits a substantial preference for N-palmitoylethanolamine (PEA) over other NAEs, is activated by TRITON X100™ (registered trademark by Union Carbide; 4-octyl-phenol polyethoxylate) and dithiothreitol (DTT). Remarkably, NAAA has lower sensitivity to inhibition with phenylmethylsulfonyl fluoride and methylarachidonyl fluorophosphonate. While the gene for NAAA has been cloned and the corresponding polypeptide is relatively well characterized (see e.g., J Biol Chem (2005), Vol. 280, No. 12, pages 11082-11092), the functional properties of NAAA in mammals are not well understood.
While numerous FAAH inhibitors have been identified in the literature (see e.g., Eur J Pharmacol (2007), 565(1-3); pages 26-36; J Enz Inhib and Med Chem (2003), 18(1), pages 55-58; Arch Biochem Biophys (1999), 362(2), pages 191-196), no inhibitors are currently reported for NAAA. Moreover, as FAAH and NAAA are not structurally closely related, it is not expected that FAAH inhibitors will provide significant inhibition of NAAA.
Therefore, while numerous compositions and methods of treating and prevention of pain and inflammation are known in the art, all or almost all of them suffer from one or more disadvantages. Consequently, there is still a need to provide improved composition and methods to treat and prevent pain and inflammation.